Recruitment
of children with severe developmental disorders for which no underlying cause
has been identified and their families to the DDD project began
in 2011. The aim was to use genome-wide microarray
and whole exome
sequencing and analysis to attempt to find a genetic diagnosis in children
from 12,000 families. Besides being of immediate importance to the families
involved, the project is also a flagship demonstration of the potential value
of large-scale DNA sequencing and analysis as diagnostic tools in healthcare.
It also has the backing of the current national network of 24 regional genetics
laboratories.

The value of a diagnosis

Finding
a cause for developmental disorders is desirable for family members, for a
number of reasons. It can in some cases help inform medical care and prognosis,
for example by suggesting other complications that may be present. In many cases
it allows clinical geneticists to evaluate the risk that future siblings might also
be affected, important information for parents considering whether to have more
children. Perhaps most compellingly, it can ‘end the diagnostic odyssey’ – ongoing
medical investigations, some potentially quite invasive, to attempt to make a
diagnosis. Removing the need for further testing may therefore remove a
significant burden from patients, families and indeed health services. Finally,
some families find psychological relief just in having a cause of their child’s
condition identified; it may also be useful in accessing appropriate social
care and educational support services.

Improving diagnostic rates

The
first results from the project have now been published in The Lancet, the findings from 1,133 familiesbased on genome-wide microarray
analysis focused on 1,100 genes previously linked with developmental disorders,
as well as whole exome sequencing and careful description of the observed
clinical symptoms in each patient. Typically, around 80,000 genomic variants of
potential interest were initially identified, of which a few hundred were rare
and expected to have a functional effect. The geneticists were able to identify
a genetic cause of disease in 27% of cases, mostly new mutations not previously
associated with disease. The expectation is that this diagnostic rate will rise
further as more and more new variants are identified in patients as potentially
or definitely causing disease (pathogenic).

Implications for genomic medicine

The DDD
project is immensely valuable in having created and tested a viable,
cost-effective pipeline for genome-wide sequencing, analysis and investigation and feedback of results. Sequencing parents as well as affected
children in rare disease investigation proved a good approach, reducing the
number of sequence variants requiring appraisal for potential pathogenicity
ten-fold compared with sequencing the children alone.

The
workflow process developed for the project is said to be scalable (ie. transferrable to large-scale use)
and clinically useful, with the authors stating that ‘we hope that it will act as a prototype for the translation of diagnostic
genome sequencing into the clinic for a range of rare diseases’. Importantly, the system can be used to reanalyse patient data,
potentially yielding more diagnoses later on as knowledge expands – information
that should be of significant interest for the 100,000 Genomes Project, a research initiative that is
intended to create the basis for genomic medicine within the NHS in England.

Lead author Dr Caroline Wright said: “The
project has shown that large-scale genome-wide testing, which brings enormous
benefits to patients and families, is both effective and affordable”.

The issue of
incidental findings

An additional area explored by the DDD project, which will continue to
recruit patients and families until April next year, is that of unexpected or
incidental findings (IFs) – significant health-related information unrelated to
the condition under investigation, for example a BRCA1/2 mutation associated with hereditary breast ovarian cancer
syndrome. It was decided that IFs would not
be returned to families by the clinicians who discussed diagnostic results
with them.

However, a linked project also examined views on the sharing of incidental
findings, using an online survey
to gather information from nearly 7,000 people (public, health and genetics
professionals) from 75 different countries on their expectations. It was reported that the vast majority of respondents felt
that IFs should be made available to research participants – but not actively
sought.

Although this was in the context of a research projec t, the distinction
between research and clinical spheres is likely to remain blurred in genomics
for some years to come. It is therefore relevant to note that the survey
conclusions is not contrast markedly to the policy
adopted by US genetic health professionals who favour active, opportunistic
screening for unrelated but medically significant variants in the context of
genome sequencing, whilst being consistent with that recently
recommended by the PHG Foundation Realising
Genomics project. Will the 100,000 Genomes Project adopt a similar line,
likely to be backed by NHS professionals – or opt for a novel, US-led approach instead?